BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination
Laurent Derré, … , Daniel Olive, Daniel E. Speiser
Laurent Derré, … , Daniel Olive, Daniel E. Speiser
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):157-167. https://doi.org/10.1172/JCI40070.
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Research Article

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

Abstract

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen–specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen–specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen–specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM–mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

Authors

Laurent Derré, Jean-Paul Rivals, Camilla Jandus, Sonia Pastor, Donata Rimoldi, Pedro Romero, Olivier Michielin, Daniel Olive, Daniel E. Speiser

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Figure 1

BTLA (CD272) is downregulated with progressive CD8+ T cell differentiation, except in tumor antigen–specific CD8+ T cells.

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BTLA (CD272) is downregulated with progressive CD8+ T cell differentiati...
Direct ex vivo analysis of CD8+ T cells from PBMCs by flow cytometry. (A) Representative examples of BTLA expression by Melan-AMART-1– and virus-specific (EBV, CMV, and influenza virus [FLU]) CD8+ T cells from healthy donors (HD) and melanoma patients. BTLA+ T cells were distinguished from BTLA– T cells using a threshold established according to the autologous naive T cell subset, which is always BTLA positive. Numbers indicate percentage of positive or negative cells. (B) Comparison of BTLA expression on total CD8+ and virus- and Melan-A–specific T cells, from healthy individuals and unvaccinated melanoma patients. **P < 10–2 for each of the 2 populations of Melan-A–specific T cells compared with all 5 other populations. (C–E) BTLA expression in subsets of CD8+ T cells of healthy individuals (n = 58), upon definition of early and late differentiation stages by CD45RA and CCR7 expression (i.e. naive [N, CD45RA+CCR7+], central memory [CM, CD45RA–CCR7+], effector memory [EM, CD45RA–CCR7–], and effector memory RA+ [EMRA, CD45RA+CCR7–] cells), gated as shown in C; a representative example demonstrates the narrow positive peak observed in phenotypic naive cells. (D) Statistical assessment of BTLA+ CD8+ T cell subsets. (E) GMFI data, showing results compatible with those presented in D. Overall GMFI was determined by including the whole range from BTLA-negative to -positive cells, as shown in C. GMFI data were normalized to values determined in autologous naive CD8+ T cells.